Abuse-resistant controlled-release opioid dosage form

ABSTRACT

Abuse-resistant, controlled release opioid tablets are a combination containing an opioid antagonist such as naloxone at a level above that needed to suppress the euphoric effect of the opioid, if the combination were crushed to break the controlled release properties causing the opioid and opioid antagonist to be released as a immediate release product as a single dose. The controlled release nature of the table prevents the accumulation of orally effective amounts of opioid antagonist when taken normally. The opioid antagonist is contained in a controlled-release matrix and released, over time, with the opioid.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/280,621, filed Sep. 29, 2016, which is a is a continuation of U.S.patent application Ser. No. 15/159,737, filed May 19, 2016 (now issuedas U.S. Pat. No. 9,480,685), which is a continuation of U.S. patentapplication Ser. No. 15/015,019, filed Feb. 3, 2016 (now issued as U.S.Pat. No. 9,345,701), which is a continuation of U.S. patent applicationSer. No. 14/859,200, filed Sep. 18, 2015 (now issued as U.S. Pat. No.9,283,221), which is a continuation of U.S. patent application Ser. No.14/725,379, filed May 29, 2015 (now issued as U.S. Pat. No. 9,168,252),which is a continuation of U.S. patent application Ser. No. 14/205,204,filed Mar. 11, 2014 (now issued as U.S. Pat. No. 9,056,051), which is acontinuation of U.S. patent application Ser. No. 13/777,537, filed Feb.26, 2013 (now abandoned), which is a continuation of U.S. patentapplication Ser. No. 13/494,431, filed Jun. 12, 2012 (now abandoned),which is a continuation of U.S. patent application Ser. No. 11/901,232,filed Sep. 14, 2007 (now abandoned), which is a divisional of U.S.patent application Ser. No. 10/143,111, filed May 10, 2002 (nowabandoned), which claims benefit of priority to U.S. ProvisionalApplication No. 60/290,439, filed May 11, 2001.

FIELD OF THE INVENTION

The present invention relates to controlled-release analgesicpharmaceutical formulations. More specifically, the invention relates toabuse-deterring controlled-release analgesic tablets.

Opioid compounds have long been known both for their powerful analgesicproperties, and for their strong potential for abuse. While highlyeffective at controlling pain, opioids can also be addictive. Abuse ofopioids, particularly heroin, but also including morphine, codeine,oxycodone, hydromorphone, oxymorphone, and others, is a problem inmodern society. Opioid addicts can obtain drugs from a variety ofillicit sources. These street drugs are of questionable quality.Therefore, to potential abusers, prescription pharmaceutical opioids canbe particularly attractive as a drug source because of their high purityand dependable dosage.

Abusers extract the pharmaceutical opioid, and other constituents, fromthe tablets. To do so, the tablets are crushed and often dissolved. Theresult may be further treated before it is ultimately injected orsnorted to achieve a “high”. This type of intravenous or intranasalabuse is well documented.

The potential for abuse of pharmaceutical opioids is not a new problem.To combat the effects of opioid abuse, opioid antagonists have been usedto block the euphoria associated with opioid abuse, and to inducewithdrawal symptoms in addicts. One opioid antagonist used previously,and even now, is naloxone. Naloxone is a powerful antagonist of theopioid receptor. Naloxone is highly effective when taken parenterally,but poorly effective when taken orally because of its metabolism in theliver and, thus, has a high oral:parenteral potency ratio. When injectedin humans, amounts as small as 0.2-0.4 mg can block the opioid receptorsand prevent the user from experiencing the drug's effects, whetheranalgesia or mood alteration, euphoria. Because of the highoral:parenteral potency ratio (˜100) the antagonist action of oral dosesof naloxone is much lower than the action of injections of naloxone.Because antagonists such as naloxone are less effective when takenorally, they have not been used to deter oral abuse and have beenlimited to deterring parenteral or intranasal abuse.

Recently however, a new form of abuse of opioid agonists has emergedinvolving oral abuse instead of abuse by injection or snorting. Thispractice has emerged largely because of the availability of high-opioidcontent controlled release (CR) formulations. “Chewing” involvescrushing the opioid formulation and taking the entire contents, meantfor 2 or more doses, at once. This practice releases all the opioid atonce to generate a “high.” The crushing may take place in the mouth assuggested by the name, but also may occur by other means to make theopioid readily available including, crushing or dissolving the tabletprior to injection or administered intranasally.

Recently, high potency prescription opioid tablets containing largemilligram doses of opioids have been introduced. These tablets arecontrolled release tablets and are designed to provide pain relief for12 hours or more. Because the tablets have action over a long timeperiod (12 hours instead of 4 hours for immediate release tablets), thetablets contain much higher quantities of opioid compounds. Forpotential abusers, these tablets are very attractive. Their high dosagesmake them a compact way to access large amounts of opioid. The fact thatthey are pharmaceuticals guarantees both the quality and quantity ofdrug in the tablet. Thus, the potential abuser knows he or she isobtaining a high purity drug in a known dosage. Prior oral opioid dosageformulations contained relatively low doses of opioid and were notgenerally targets for oral abuse. Their immediate release formulationsrelease the opioid all at once, but with low amounts of opioid thatwould not be sufficient for oral abuse without putting several lowdosage units together. In contrast, abusers have found that the new CRtablets contain large doses of opioid, which can be abused orally bychewing the tablets or crushing them to release all of the opioid at onetime (immediate release). The present invention deters such oral abuse.

Oxycontin®, a controlled release oxycodone tablet from Purdue Pharma, isavailable in strengths as high as 160 mg oxycodone per tablet. The highopioid content makes these tablets especially attractive to abusers.Illegal trade in controlled release opioid tablets is becoming moreprevalent. In order to obtain a euphoric effect (high) from suchtablets, an abuser may crush the tablet and extract the opioid compoundby dissolution for injection, or intranasal administration. Also, theabuser can achieve a euphoric effect from the drug by simply taking thedrug orally, after chewing the tablet or grinding it to break thecontrolled release matrix and converting it to an immediate releaseproduct. Therefore, it would be desirable to have a formulation whichwould prevent the oral abuse of controlled release tablets if crushed toconvert it to an immediate release product, without significantlyaffecting the analgesic action of opioid compounds in the intactcontrolled release tablet.

WO 01/58447 discloses pharmaceutical combinations of opioid agonists andantagonists in a controlled release matrix. The antagonist is presentand released in amounts, over time, that attenuate or reduce the sideeffects of the opioid agonist, yet in amounts insufficient to block theopioid effect. The preferred antagonist is Naltrexone, which is highlyeffective when administered orally or parenterally. The antagonist isreleased only in very small amounts, 100-1000 times less than theopioid. WO '447 is silent with respect to including an anti-abusiveamount of antagonist in the dose to prevent abuse. The intravenous useof small amounts of naloxone, 0.25 or 1 μg kg⁻¹hr⁻¹, is also disclosedas having attenuating effects.

WO '447 does not present release rates for the antagonist in its CRformulation, but directs those skilled in the art to the Crain patents(U.S. Pat. Nos. 5,767,125; 5,580,876; 5,512,578; and 5,472,943). TheCrain patents collectively disclose instant release formulations with“ultra-low” doses of certain antagonists to selectively block only theexcitatory opioid receptors to attenuate opioid side effects, withoutblocking inhibitory receptors, which would lead to opioid blocking.These doses are on the order of pico-molar amounts. Crain '578 suggeststhat only naltrexone is useful in oral administration and that 1 μgdoses are sufficient for attenuating opioid side effects by selectivelyblocking the excitatory opioid receptors and leaving the inhibitoryopioid receptors free for receiving the opioid agonist (which may beadministered in lower than normal doses with similar analgesic effect).The normal oral dose of naltrexone is about 50 mg versus “ultra low”does of 1 μg of naltrexone described in Crain '578 patent.

The prior art does not discuss controlled release formulation containingagonist and antagonist to deter abuse. Accordingly, there is a need fora composition that deters abuse in the high opioid-content controlledrelease formulation prevalent today.

SUMMARY OF THE INVENTION

Abuse-resistant, controlled release opioid tablets are a combinationcontaining an opioid antagonist having a high oral:parenteral potencyratio (i.e. oral:parenteral >1), such as naloxone, at a levelinsufficient to block the opioid effects or to attenuate the opioidside-effects in the controlled release formulation administered over anextended period, but above that needed to suppress the euphoric effectof the opioid if administered all at once. If the combination tablet iscrushed to break the controlled release properties, the opioid andopioid antagonist is released as an immediate release product in asingle dose, and the antagonist blocks the euphoric effects of theagonist. The opioid antagonist is contained in a controlled-releasematrix and released over time, with the opioid agonist.

DETAILED DESCRIPTION OF THE INVENTION

The present invention employs the principle that certain opioidantagonists are ineffective in low oral doses. Therefore, one canadminister a low oral dose over a long period of time (controlledrelease) from a tablet containing a large, orally effective amount ofantagonist, without adversely affecting the action of the opioid.However, if the antagonist is administered all at once, it will blockthe opioid effect and may induce withdrawal in dependent individuals.

The present invention is intended for use in controlled releasecompositions. The term, “controlled release” or “CR” when used herein,is intended to refer to tablets intended to release an activepharmaceutical ingredient over an extended period of time, usually over4 hours, generally 8-12 or up to 24 hours. One method of determiningthis is to check the intended dosing schedule. Any tablet intended to betaken less frequently than once every four hours should be consideredcontrolled release regardless of labeling as controlled release,sustained release, extended release, etc. Often, these tablets containpolymeric matrices which may be cross-linked. Examples of suchcontrolled release formulations are the Contin® system, produced byPurdue Fredrick Pharmaceuticals, or the TimerX® system by PennwestPharmaceuticals. Other controlled release polymers can also be used,such as methacrylate (Eudragit®), hydroxylpropyl methylcellulose (HPMC),or Carbopol®. The present invention may be used with these or othercontrolled release formulations.

The tablet of the present invention contains an opioid agonist in acontrolled release matrix, along with an opioid antagonist. Theantagonist is present at such a level, and dispensed at such a rate,that it will not block the action of the opioid agonist when an intactcontrolled release tablet is taken orally. Crushing the tablet willrelease sufficient antagonist all at once as an immediate releaseformulation to block the opioid response and also, induce abstinence.Antagonists need to reach an effective dose to work, so their slowrelease coupled with fast metabolism means they are maintained atineffective, low levels in normal, recommended, therapeutic, non-abusiveuse. This low level of antagonist can be released over a long timeperiod without affecting the therapeutic action of the opioid agonist.Even with sustained release over such long periods, the antagonist doesnot accumulate to blocking levels, since it is metabolized before it canaccumulate to such levels. Because of the nature of the opioidantagonist action, the level of antagonist should be varied with theopioid dosage of the tablet. Also, depending on the antagonist, theoral:parenteral potency ratio, and the release rates, the levels ofantagonists employed will vary. Regardless, there should be sufficientantagonist to block the opioid effect (high) and induce withdrawal independent individuals, if the tablet is crushed, converting theformulation to immediate release. Under normal conditions, the releaserate is not sufficient for blocking the opioid effect nor suitable forselectively blocking the excitatory opioid receptors to attenuate opioidside effects. For Naloxone, the presently preferred antagonist, it isbelieved that 15 mg (immediate release) should begin to block the opioidreceptors and initiate withdrawal.

The specific opioid agonists, antagonists, CR matrices, and thecombinations disclosed herein are merely exemplary. Other agonists,antagonists, matrices, and combinations may be used in conjunction withthe teachings herein.

The opioid agonist can be any agonist in general use as an analgesic,including, but not limited to, morphine, oxycodone, levorphanol,meperdine, hydrocodone, codeine, dihydrocodeine, hydromorphone,propoxyphene, methadone, and oxymorphone. Specifically, any addictiveopioid in a controlled release dosage form is the target of the presentinvention. Most particularly, controlled release oxycodone has recentlybeen the target of abuse, and would therefore make a good candidate foruse in the present invention. Of course, the release rate of the opioidagonist is established to achieve the desired analgesic effect.

Potency of the antagonist is measured as the oral:parenteral potencyratio, which indicates the amount of antagonist required orally toachieve an equivalent effect to an effective parenteral dose. Forexample, an antagonist having an oral:parenteral potency ratio of 10:1requires 10 times the parenteral dose to be effective orally. The opioidantagonists used herein will have greater antagonistic effect whenadministered parenterally than when administered orally (oral:parenteralpotency ratio >1). Accordingly, the desired antagonists block the opioideffect and induce withdrawal when administered at relatively low levelsparenterally or intranasally. At the same time, these antagonistsrequire relatively large levels to be effective when administered orallyfor recommended, therapeutic use. Thus, effective parenteral/intranasaldoses are ineffective when administered orally. Preferably, theoral:parenteral potency ratio is at least approximately 10:1, morepreferably at least approximately 25:1, and most preferably at leastapproximately 100:1 as is the case with Naloxone. Appropriate opioidantagonists having substantially greater effectiveness when administeredby injection than when administered orally, include, but are not limitedto: naloxone; naltrexone;N-cyclopropylmethyl-7,8-dihydro-14-hydroxynormorphinone or21-cyclopropylz,-(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrahydrooripavine (ordiphenorphine); and the pharmaceutically-acceptable salts thereof.

It has previously been known that opioid antagonists, such as naloxone,can block opioid receptors and reduce or eliminate the effect ofopioids. Such antagonists are useful in treating opioid overdoses and tohelp treat addiction, in some cases. By blocking opioid receptors, theantagonists reverse and block the response to opioids. The highoral:parenteral potency ratio antagonists, such as naloxone, while veryeffective when injected, are significantly less effective when takenorally. Therefore, a dosage form designed for oral administration canhave a significant amount of opioid antagonist, without adverselyaffecting the therapeutic efficacy of the opioid. Similarly, theselevels of antagonists do not attenuate the side effects of the opioid.Such an antagonist would be effective in deterring intravenous orintranasal abuse when present in low levels, but would be ineffective indeterring oral abuse. Were the tablets to include sufficient antagonistto deter oral abuse, the antagonist would also reduce or inhibit thetherapeutic efficacy of the drug. A tablet containing an orallyeffective amount of antagonists in a CR formulation releasingineffective amounts of antagonist under normal use would be effectiveagainst both oral and parenteral abuse, without minimizing theeffectiveness of the opioid under normal use.

The amount of antagonist in the composition will depend on the relativestrength of the antagonist, the amount and strength of the opioid, therelease rate of the antagonist, and the oral:parenteral potency ratio.In any event, the combination of antagonist type, oral:parenteralpotency ratio, quantity, and release rate do not result in blockage ofthe opioid effect or attenuation of its side effects, when administeredorally in its intended, intact dosage form.

Strengths of controlled release opioid tablets vary with the particularopioid used. In the case of oxycodone, strengths of 10, 20, 40, 80, and160 mg may be used in a controlled release formula. The amount of opioidantagonist (such as naloxone) in such a tablet may also vary from about2 mg to 40 mg or more. There should be at least 5 to 20 mg (preferably10 to 20 mg) of naloxone in a tablet to prevent oral abuse by chewing anumber of small, low dose tablets or a higher strength tablet. That is,the accumulation of an abusive dose by combining 2 or more low-dosetablets should also accumulate an effective amount of antagonist. Higherdose opioid tablets should contain an effective amount of antagonistwithout accumulation. Prevention of abuse by parenteral or intranasaladministration will also be accomplished, since in the case of injectionor snorting, only about 0.2 to 0.4 mg naloxone is needed to antagonizethe opioid effect, to induce abstinence in dependent individuals, and toprevent abuse. Therefore the larger amount needed to prevent oral abusewill necessarily prevent abuse by injection or intranasal administrationas well.

For oxycodone tablets of 10 or 20 mg tablet strength, the amount ofnaloxone, opioid antagonist used can range from 5 to 40 mg. As thetablet strength rises, the ratio of opioid to opioid antagonist variesfrom 1:3 to 4:1, since a 160 mg opioid tablet may contain 80 mg opioidantagonist. Although the ratio can vary, it is preferable to select oneratio for all tablet strengths. Physicians prefer to titrate patientsusing several low dose tablets which add up to the desired dosage. Thisis easiest if a constant ratio is maintained. Thus, a constant ratioacross tablet strengths is useful even though that ratio can be anyappropriate ratio in the range set forth above.

Drug abusers are creative when finding ways to defeat anti-abusivemeasures. Currently, several methods of oral abuse are contemplated. Asdiscussed above, it should be remembered that the compositions of theinvention contain sufficient antagonist to be effective orally and,therefore, necessarily contain a parenterally or intranasally effectiveblocking amount. Accordingly, parenteral and intranasal abuse are notdiscussed here.

Abusers may “chew” a single large dose tablet to achieve instant releaseof an abusive dose of opioid. Compositions containing these abusiveamounts of opioid should contain enough antagonist to block oral abuseby “chewing.”

Two or more lower dose tablets may be “chewed” together to achieve anabusive dose. To the extent that each tablet itself does not contain anorally, effective amount of antagonist, when combined to an abusivedose, the combined antagonist should be orally effective. That is if,for example, a 10 mg tablet is not sufficient to achieve a high, it neednot contain the full orally effective amount of antagonist. If two 10 mgtablets are sufficient for a high, they then should contain a combinedamount of antagonist which is effective orally for blocking the opioideffect.

Additionally, two or more high-dose tablets could be taken orally,without crushing, to achieve a “high.” Such a combination would takeadvantage of the CR properties to sustain a high for the entire dosageperiod up to 12 hours. This type of abuse is uncommon since most abuserswant the instant high or rush afforded by the immediate release of thecrushed tablets. Such a combination, according to one embodiment of theinvention, should also release a blocking amount of antagonist whentaken orally without chewing. This arrangement would also prevent thedire effects of accidental overdose. Although this type of arrangementwould be beneficial in many situations, it could limit a prescribingdoctor's options, and therefore, may not be appropriate in allsituations. Tablets according to this embodiment are not preferred, butare certainly within the scope of the invention.

Tablets according to the invention may take into consideration any ofthe above abusive regimes individually or any combination thereof.

The basic underlying premise of the invention is that the tabletcontains 1) an amount of antagonist which is orally effective forblocking the opioid effect and 2) that the antagonist is available,normally, only at levels that are ineffective to block the opioid effector to attenuate the opioid side-effects. One of the ways to achieve thisis to control the release rate of the antagonist. The release rate ofthe antagonist is best thought of in terms of a percent of the releaserate of the opioid agonist. The rate is controlled between approximately100%-0% of the release rate of the opioid, preferably 100%-25%. Table 1shows release rates of opioid and antagonist as % released. In the caseof 0%, the antagonist is never released unless the tablet is crushed.But, that is the subject of another application.

In the case of Naloxone, the short half-life (about one hour) ensuresthat the Naloxone does not accumulate to blocking levels, even whenreleased at the same rate as the opioid. In slower release formulations(50% and 75%), the unreleased portion remaining after 10-12 hours passesto the large intestine where the absorption rate is much slower than inthe stomach and small intestine. Accordingly, the amount of antagonistreleased beyond 10-12 hours does not contribute to any blocking orattenuating effect.

These release rates ensure that under normal usage the antagonist has noblocking or attenuating effect. Simultaneously, however, an orallyeffective blocking dose of the antagonist is present in the event thatthe CR properties are defeated.

The type and application of CR matrix used will determine release rates.Manipulation of release rates, even of two compounds with two differentrates is known in the art. Any known or later developed CR techniquesmay be used. It is important to remember though, that the antagonistshould not be readily distinguishable or separable from the agonist,since would be abusers could possibly use mechanical separationtechniques prior to defeating the CR formulation.

TABLE 1 Release Rates from CR formulation ANTAGONIST (as % of AGONISTrelease rate) AGONIST 100% 50% 25%  1 HR 20-30% 20-30% 10-15%  5-7.5%  4HRS 60-70% 60-70% 30-35% 15-17.5% 10 HRS  >90%   >90%  45-50% 22.5-25%

Release rates are a percentage of agonist or antagonist with respect toits total content in the composition.

The tablets may be made by any traditional method of manufacture ofcontrolled release tablets. Two principal processes are wet process(including wet granulation) and dry process (including direct mixing androller compaction process.) Exemplary compositions for those processesare reproduced below.

TABLE 2 Preferred Naloxone Ranges for Differing Strengths of OxycodoneTablets Oxycodone (mg) 10 20 40 80 160 Naloxone (mg) 2-10 4-20 8-4016-80 20-160

For oxymorphone, the doses for controlled release tablets may be 10, 20,or 40 mg and the naloxone dose ranges may be the same as set forth foroxycodone.

The preferred oxycodone:naloxone ratio is 5:1 to 1:1.

TABLE 3 Formula 1 of Oxycodone HCl 10-mg Tablets with Naloxone Componentmg/Tablet percent (by wt) Oxycodone Hydrochloride 10.00  2.22% Naloxone10.00  2.22% Lactose (spray-dried) 281.50 62.56% HydroxypropylMethylcellulose, 135.00 30.00% K100M Silicone Dioxide 9.00  2.00%Magnesium Stearate 4.50  1.00% Total: 450.00 100.00% 

TABLE 4 Formula 2 of Oxycodone HCl 10-mg Tablets with Naloxone Componentmg/Tablet percent (by wt) Oxycodone Hydrochloride 10.00  3.77% Naloxone10.00  3.77% Lactose (spray-dried) 157.55 59.45% HydroxypropylMethylcellulose, 79.50 30.00% K100M Silicone Dioxide 5.30  2.00%Magnesium Stearate 2.65  1.00% Total: 265.00 100.00% 

TABLE 5 Formula 3 of Oxycodone HCl 10-mg Tablets with Naloxone Componentmg/Tablet percent (by wt) Oxycodone Hydrochloride 10.00  8.33% Naloxone10.00  8.33% Lactose (spray-dried) 60.40 50.33% HydroxypropylMethylcellulose, 36.00 30.00% K100M Silicone Dioxide 2.40  2.00%Magnesium Stearate 1.20  1.00% Total: 120.00 100.00% 

Alternate compositions may also be used. Preferably, tablets accordingto the present invention will have the following compositions:

Material Quantity (%) Oxycodone Hydrochloride, USP  2.000-35.000Naloxone  2.000-20.000 Microcrystalline Cellulose, NF (Avicel PH102)10.000-50.000 Ammonia Methacrylate Copolymer, 30.000-70.000 NF (EudragitRSPO) Colloidal Silicon Dioxide, NF (Cab-O-Sil)    0-5.000 Sodium LaurylSulfate, NF    0-5.000 Magnesium Hydroxide, USP    0-2.000 Povidone, USP   0-15.000 Stearic Acid, NF    0-5.000 Magnesium Stearate, NF   0-5.000

Dissolution was conducted according to USP XXIV Apparatus 3(Reciprocating Cylinder) for Formulation 1-3. The apparatus 3 is tosimulate the gastrointestinal conditions of human. The 1st hour is at pH1.2 of 0.1N HCl. The 2nd and 3rd hours are at pH 4.5 of 10 mM ofpotassium phosphate monobasic. The conditions after the 3rd hours are atpH 6.8 of 10 mM of potassium phosphate monobasic. All dissolutionvessels contain 250 mL of dissolution solution. The dip rate is set at10 dips per minute. The bath temperature is set at 37.5° C. The HPLCparameters are set as follows: Column-Inertsil ODS 3, 50 mm×4.6 mm, 3 μmparticle size. Mobile phase: 80% 30 mM sodium hexanesulfonate pH3.0+/−1, 20% acetonitrile. Injection volume is 75 μL. Column temperatureis 35° C., Flow rate is set at 1.0 mL/min. Wavelength is set at 225 nm.Run time is 5.5 minutes.

Dissolution results for Formulation 1-3 were as follows:

Formulation 1 Tablet not Crushed Tablet Crushed % Oxycodone % Naloxone %Oxycodone % Naloxone Time Dissolved Dissolved Dissolved Dissolved 0 0.00.0 0.0 0.0 1 29.8 27.8 88.2 94.6 2 47.8 45.4 3 59.8 57.4 4 68.5 65.9 891.1 87.5 12 100.7 97.9

Formulation 2 Tablet not Crushed Tablet Crushed % Oxycodone % Naloxone %Oxycodone % Naloxone Time Dissolved Dissolved Dissolved Dissolved 0 0.00.0 0.0 0.0 1 40.1 37.0 104.9 102.8 2 63.2 60.3 3 77.3 75.3 4 86.5 85.28 105.6 106.1 12 110.5 112.6

Formulation 3 Tablet not Crushed Tablet Crushed % Oxycodone % Naloxone %Oxycodone % Naloxone Time Dissolved Dissolved Dissolved Dissolved 0 0.00.0 0.0 0.0 1 59.0 52.5 100.5 90.9 2 85.4 78.0 3 97.4 90.3 4 102.5 95.98 105.4 99.7 12 105.4 99.8

From these tests, it is evident that under normal, non-crushing use, theamount of antagonist, here naloxone, released over time is insufficientto block the opioid effect. Even Example 3, which has the highestinitial release rate of antagonist, only makes about 5 mg naloxoneavailable in the first hour. Due to the short half-life of naloxone, andthe slow release rate, the antagonist does not accumulate in the body toa level that blocks the opioid effect. On the other hand, in the crushedtablet, substantially all of the antagonist is available in the firsthour. Thus, an opioid blocking amount of antagonist is readily availableto deter oral and other forms of abuse. Regardless of the antagonistused, the combination of the antagonist content, the release rate, andthe antagonist half-life achieves the goals of the invention to blockthe opioid effect when administered as for instant release, yet notblocking the opioid effect when administered as intended and recommendedas a controlled release formulation.

It is well known that the various opioids have differing relativestrengths. Often, these are compared and related to a standard fordetermining relative doses of each. Although this application discussesopioid content in terms of oxycodone, those skilled in the art willreadily appreciate that other opioids, stronger and weaker, can be usedin equivalent dosage amounts. Likewise, the antagonist is similarlyselected and dosed.

The scope of the invention is not limited to the above examples, whichare provided only for purposes of illustration. The above description iswritten in the context of a tablet. Other oral dosage forms, capable ofbeing made in CR formulations may be used. Among the oral dosage formsavailable are capsules, caplets, microspheres, gel caps and even liquidformulations.

1. A method of treating a patient with an opioid agonist comprising:providing an analgesic composition in capsule form comprising, in % byweight: opioid agonist; and an opioid antagonist in an amount that isorally effective to block an opioid effect caused by the opioid agonist;ammonio methacrylate copolymer, NF; up to about 5% sodium laurylsulfate, NF; and up to about 5% magnesium stearate, NF; wherein saidcomposition comprises 1) a controlled release formulation containing theopioid agonist that controls the release rate of the opioid agonist suchthat therapeutic agonist levels are maintained and 2) a controlledrelease formulation containing the antagonist which is not releasedunless the capsule is crushed but is released as an immediate releaseformulation when the capsule is crushed; maintaining the capsulesubstantially intact; and orally administering the substantially intactcapsule to a patient.
 2. The method according to claim 1, wherein saidopioid agonist is selected from the group consisting of morphine,oxycodone, levorphenol, meperdine, hydrocodone, codeine, dihydrocodeine,hydromorphone, propoxyphene, methadone, and oxymorphone and the opioidantagonist is selected from the group consisting of naloxone,naltrexone, N-cyclopropylmethyl-7,8-dihydro-14-hydroxynormorphinone, and2-cyclopropylz,-(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrayhydrooripavine (ordiphenorphine) and the pharmaceutically-acceptable salts thereof.
 3. Themethod according to claim 1, wherein the opioid agonist is apharmaceutically acceptable morphine and said opioid antagonist isnaltrexone.
 4. The method according to claim 1, wherein the opioidantagonist has a greater antagonistic effect when administeredparenterally than when administered orally.